Qualitative And Quantitative Studies Of Chirality Inversion In Hybrid Arylamide Folds And Their Similar Helical Structures By High-performance Molecular Dynamics Simulations

Conformational inversion of foldamers has been shown to transmit signals across the lipid membrane.Helicity switching is critical to fulfilling this function.Despite the importance of the conformational inversion,the mechanism that underlies the helicity switching process remains unclear.And there is no way to demonstrate this mechanism experimentally.In this paper,a hybrid arylamide foldamer and its similar helical structure(2T)have been studied at the atomic level using molecular dynamics simulations.By studying the complex mechanisms by which foldamers move from right-handed to left-handed,we hope to improve our understanding of helical switching and thus help design helical oligomers with new sequences and functions.In this paper,the feasibility of high performance molecular dynamics simulation of chiral inversion in hybrid aryl amide foldamers and their similar helical structures is investigated.Specific research contents are as follows:1.Qualitative analysis.The helical inversion of the foldamer is constituted by helicity switching processes of two segments connected by a flexible methylene linker.The chirality switching process of the first segment and the second segment follows the hopping mechanism and the thorough-unwinding-rewinding mechanism,respectively.According to the geometric analysis and calculation of the composition interaction,the energy barrier at each stage with the smallest free energy path is caused by the weakening of the van der Waals forces(π-π stack)interaction between the monomers.This weakening can be attributed to the reduction of contact area during the expansion of the tetramer in the folded body.The 2T structure consists of two conjugated nuclei and three flexible side chains.The two-dimensional and three-dimensional free energy landscapes characterizing 2T isomerization reveal a four-stage helicity switching processes.The four stages include the flip of the three outer aromatic rings of the top layer and the rotation of the lower aromatic rings relative to the top layer.When the second benzene ring flips,the highest energy barrier against right-handed and left-handed helical switching appears.Structural analysis showed that the flip of the ring stretched the side chain,resulting in the deformation of the conjugated nucleus,the distortion of the dihedral angle in the side chain,and the redirection of the amine groups attached to the chain.2.Quantitative analysis.For the hybrid arylamide foldamer,a three-dimensional free energy diagram was determined to characterize the helical transformation of the segments.The height of the highest free energy barrier is within this range(8.0 < s <9.0),and the maximum energy barrier that hinders the right-handed and left-handed helicity switching is estimated to be 25.1 kcal / mol,which is consistent with the experimental measurements.For the 2T structure,the height of the maximum free energy barrier at the second stage is estimated to be 7.4 kcal / mol,which is consistent with the experimental results.